Schizophrenia is a major psychiatric disorder affecting up to 1% of the population. It is found at similar prevalence in both sexes and is found throughout diverse cultures and geographic areas (1; 2). The World Health Organization found schizophrenia to be the world's fourth leading cause of disability (3; 4) that accounts for 1.1% of the total DALYs (Disability Adjusted Life Years) and 2.8% of YLDs (years of life lived with disability)(4). It was estimated that the economic cost of schizophrenia exceeded US$ 19 billion in 1991, more than the total cost of all cancers in the United States. Effective treatments used early in the course of schizophrenia can improve prognosis and help reduce the costs associated with this illness.
The clinical syndrome of schizophrenia comprises discrete clinical features including positive symptoms (hallucination, delusions, disorganization of thought and bizarre behaviour); negative symptoms (loss of motivation, restricted range of emotional experience and expression and reduced hedonic capacity); and cognitive impairments with extensive variation between individuals (5). No single symptom is unique to schizophrenia and/or is present in every case. Despite the lack of homogeneity of clinical symptoms, the current diagnosis and classification of schizophrenia is still based on the clinical symptoms presented by a patient (6). This is primarily because the aetiology of schizophrenia remains unknown (in fact, the aetiology of most psychiatric diseases is still unclear) and classification based on aetiology is as yet not feasible. However, the clinical symptoms of schizophrenia are often similar to symptoms observed in other neuropsychiatric disorders, making accurate diagnosis difficult.
Due to the complex spectrum of symptoms presented by subjects with schizophrenic disorders and their similarity to other mental disorders, current diagnosis of schizophrenia is made on the basis of a complicated clinical examination/interview of the patient's family history, personal history, current symptoms (mental state examination) and the presence/absence of other disorders (differential diagnosis; Table 1). This assessment allows a “most likely” diagnosis to be established, leading to the initial treatment plan. To be diagnosed with schizophrenia, a patient (with few exceptions) should have psychotic, “loss-of-reality” symptoms for at least six months (DSM IV) and show increasing difficulty in functioning normally.
The ICD-10 Classification of Mental and Behavioural Disorders, published by the World Health Organization in 1992, is the manual most commonly used by European psychiatrists to diagnose mental health conditions including schizophrenia and bipolar disorder. The manual provides detailed diagnostic guidelines and defines the various forms of schizophrenia: schizophrenia, paranoid schizophrenia, hebrephrenic schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, post-schizophrenic schizophrenia, residual schizophrenia and simple schizophrenia.
The Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM IV) published by the American Psychiatric Association, Washington D.C., 1994, has proven to be an authoritative reference handbook for health professionals both in the United Kingdom and in the United States in categorizing and diagnosing mental health problems. This describes the diagnostic criteria, subtypes, associated features and criteria for differential diagnosis of mental health disorders, including schizophrenia and bipolar disorder.
DSM IV Diagnostic Criteria for Schizophrenia
A. Characteristic symptoms: Two (or more) of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated): delusions, hallucinations, disorganized speech (e.g., frequent derailment or incoherence), grossly disorganized or catatonic behavior, negative symptoms, i.e., affective flattening, alogia, or avolition. Only one Criterion A symptom is required if delusions are bizarre or hallucinations consist of a voice keeping up a running commentary on the person's behavior or thoughts, or two or more voices conversing with each other.
B. Social/occupational dysfunction: For a significant portion of the time since the onset of the disturbance, one or more major areas of functioning such as work, interpersonal relations, or self-care are markedly below the level achieved prior to the onset (or when the onset is in childhood or adolescence, failure to achieve expected level of interpersonal, academic, or occupational achievement).
C. Duration: Continuous signs of the disturbance persist for at least 6 months. This 6-month period must include at least 1 month of symptoms (or less if successfully treated) that meet Criterion A (i.e., active-phase symptoms) and may include periods of prodromal or residual symptoms. During these prodromal or residual periods, the signs of the disturbance may be manifested by only negative symptoms or two or more symptoms listed in Criterion A present in an attenuated form (e.g., odd beliefs, unusual perceptual experiences).
D. Schizoaffective and Mood Disorder exclusion: Schizoaffective Disorder and Mood Disorder With Psychotic Features have been ruled out because either (1) no Major Depressive Episode, Manic Episode, or Mixed Episode have occurred concurrently with the active-phase symptoms; or (2) if mood episodes have occurred during active-phase symptoms, their total duration has been brief relative to the duration of the active and residual periods.
E. Substance/general medical condition exclusion: The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.
F. Relationship to a Pervasive Developmental Disorder: If there is a history of Autistic Disorder or another Pervasive Developmental Disorder, the additional diagnosis of Schizophrenia is made only if prominent delusions or hallucinations are also present for at least a month (or less if successfully treated).
Schizophrenia Subtypes
1. Paranoid Type: A type of Schizophrenia in which the following criteria are met: Preoccupation with one or more delusions or frequent auditory hallucinations. None of the following is prominent: disorganized speech, disorganized or catatonic behavior, or flat or inappropriate affect.
2. Catatonic Type: A type of Schizophrenia in which the clinical picture is dominated by at least two of the following: motoric immobility as evidenced by catalepsy (including waxy flexibility) or stupor, excessive motor activity (that is apparently purposeless and not influenced by external stimuli), extreme negativism (an apparently motiveless resistance to all instructions or maintenance of a rigid posture against attempts to be moved) or mutism, peculiarities of voluntary movement as evidenced by posturing (voluntary assumption of inappropriate or bizarre postures), stereotyped movements, prominent mannerisms, or prominent grimacing, echolalia or echopraxia.
3. Disorganized Type: A type of Schizophrenia in which the following criteria are met: all of the following are prominent: disorganized speech, disorganized behavior, flat or inappropriate affect. The criteria are not met for Catatonic Type.
4. Undifferentiated Type: A type of Schizophrenia in which symptoms that meet Criterion A are present, but the criteria are not met for the Paranoid, Disorganized, or Catatonic Type.
5. Residual Type: A type of Schizophrenia in which the following criteria are met: Absence of prominent delusions, hallucinations, disorganized speech, and grossly disorganized or catatonic behavior. There is continuing evidence of the disturbance, as indicated by the presence of negative symptoms or two or more symptoms listed in Criterion A for Schizophrenia, present in an attenuated form (e.g., odd beliefs, unusual perceptual experiences).
Schizophrenia Associated Features
Features associated with schizophrenia include: learning problems, hypoactivity, psychosis, euphoric mood, depressed mood, somatic or sexual dysfunction, hyperactivity, guilt or obsession, sexually deviant behavior, odd/eccentric or suspicious personality, anxious or fearful or dependent personality, dramatic or erratic or antisocial personality.
Differential Diagnosis of Schizophrenia
Many disorders have similar or even the same symptoms as schizophrenia. The clinician, therefore, in his/her diagnostic attempt has to differentiate against the following disorders which he/she needs to rule out to establish a precise diagnosis: psychotic disorder due to a general medical condition, delirium, or dementia; substance-induced psychotic disorder; substance-induced delirium; substance-induced persisting dementia; substance-related disorders; mood disorder with psychotic features; schizoaffective disorder; depressive disorder not otherwise specified; bipolar disorder not otherwise specified; mood disorder with catatonic features; schizophreniform disorder; brief psychotic disorder; delusional disorder; psychotic disorder not otherwise specified; pervasive developmental disorders (e.g., autistic disorder); childhood presentations combining disorganized speech (from a communication disorder) and disorganized behavior (from attention-deficit/hyperactivity disorder); schizotypal disorder; schizoid personality disorder and paranoid personality disorder.
DSM IV Diagnostic Categories for Manic Depression/Bi-Polar Affective Disorder (BD)
Only two sub-types of bipolar illness have been defined clearly enough to be given their own DSM categories, Bipolar I and Bipolar II.
Bipolar I: This disorder is characterized by manic episodes; the ‘high’ of the manic-depressive cycle. Generally this manic period is followed by a period of depression, although some bipolar I individuals may not experience a major depressive episode. Mixed states, where both manic or hypomanic symptoms and depressive symptoms occur at the same time, also occur frequently with bipolar I patients (for example, depression with the racing thoughts of mania). Also, dysphoric mania is common, this is mania characterized by anger and irritability.
Bipolar II: This disorder is characterized by major depressive episodes alternating with episodes of hypomania, a milder form of mania. Hypomanic episodes can be a less disruptive form of mania and may be characterized by low-level, non-psychotic symptoms of mania, such as increased energy or a more elated mood than usual. It may not affect an individual's ability to function on a day to day basis. The criteria for hypomania differ from those for mania only by their shorter duration (at least 4 days instead of 1 week) and milder severity (no marked impairment of functioning, hospitalization or psychotic features).
If the depressive and manic symptoms last for two years and do not meet the criteria for a major depressive or a manic episode then the diagnosis is classified as a Cyclothymic disorder, which is a less severe form of bipolar affective disorder. Cyclothymic disorder is diagnosed over the course of two years and is characterized by frequent short periods of hypomania and depressive symptoms separated by periods of stability.
Rapid cycling occurs when an individual's mood fluctuates from depression to hypomania or mania in rapid succession with little or no periods of stability in between. One is said to experience rapid cycling when one has had four or more episodes in a given year that meet criteria for major depressive, manic, mixed or hypomanic episodes. Some people who rapid cycle can experience monthly, weekly or even daily shifts in polarity (sometimes called ultra rapid cycling).
When symptoms of mania, depression, mixed mood, or hypomania are caused directly by a medical disorder, such as thyroid disease or a stroke, the current diagnosis is Mood Disorder Due to a General Medical Condition, If a manic mood is brought about through an antidepressant, ECT or through an individual using street drugs, the diagnosis is Substance-induced Mood Disorder, with Manic Features.
Diagnosis of Bipolar III has been used to categorise manic episodes which occur as a result of taking an antidepressant medication, rather than occurring spontaneously. Confusingly, it has also been used in instances where an individual experiences hypomania or cyclothymia (i.e. less severe mania) without major depression.
Mania
Manic Depression is comprised of two distinct and opposite states of mood, whereby depression alternates with mania. The DSM IV gives a number of criteria that must be met before a disorder is classified as mania. The first one is that an individual's mood must be elevated, expansive or irritable. The mood must be a different one to the individual's usual affective state during a period of stability. There must be a marked change over a significant period of time. The person must become very elevated and have grandiose ideas. They may also become very irritated and may well appear to be ‘arrogant’ in manner. The second main criterion for mania emphasizes that at least three of the following symptoms must have been present to a significant degree: inflated sense of self importance, decreased need for sleep, increased talkativeness, flight of ideas or racing thoughts, easily distracted, increased goal-directed activity, excessive involvement in activities that can bring pleasure but may have disastrous consequences (e.g. sexual affairs and spending excessively). The third criterion for mania in the DSM IV emphasizes that the change in mood must be marked enough to affect an individual's job performance or ability to take part in regular social activities or relationships with others. This third criterion is used to emphasize the difference between mania and hypomania.
Depression
The DSM IV states that there are a number of criteria by which major depression is clinically defined. The condition must have been evident for at least two weeks and must have five of the following symptoms: a depressed mood for most of the day, almost every day, a loss of interest or pleasure in almost all activities, almost every day, changes in weight and appetite, sleep disturbance, a decrease in physical activity, fatigue and loss of energy, feelings of worthlessness or excessive feelings of guilt, poor concentration levels, suicidal thoughts.
Both the depressed mood and a loss of interest in everyday activities must be evident as two of the five symptoms which characterize a major depression. It is difficult to distinguish the symptoms of an individual suffering from the depressed mood of manic depression from those of someone suffering from a major depression. Dysthymia is a less severe depression than unipolar depression, but it can be more persistent.
Psychosis
Psychosis is characterized by disorders in basic perceptual, cognitive, affective, and judgmental processes. For example, one might experience delusions, hallucinations, disorganized speech, disorganized behaviour etc. A diagnosis of bipolar affective disorder does not mean that an individual will necessarily experience psychosis. Psychotic symptoms are associated with several different brain disorders, including lesions in the brain resulting from head traumas, strokes, tumours, infections or the use of illegal drugs. Psychotic symptoms may develop in serious depression.
Schizoaffective Disorder
Schizo-affective disorder is characterised by elements of both schizophrenia and bipolar disorder, it has been referred to as “schizophrenia with a mood component”. Schizoaffective disorder is characterised by concomitant symptoms of both schizophrenia and bipolar disorder to a similar degree in a given episode of illness, thus it is generally very difficult to distinguish schizoaffective disorder from bipolar disorder or schizophrenia, and the existence of schizoaffective disorder as a distinct syndrome is a controversial subject in the field. There is often a failure to diagnose schizoaffective disorder because of the complex nature of the illness. Many individuals with schizoaffective disorder are originally diagnosed with manic depression.
Schizoid personality, schizophreniform disorder, schizotypal personality and bipolar disorder (manic depression) are frequently confused and misdiagnosed. Thus, a differential diagnosis is needed to distinguish schizophrenia and bipolar disorder from other conditions that present with similar symptoms, for example schizoaffective disorder, and brief psychotic disorder (6).
Individuals with bipolar disorder meet the full diagnostic criteria for schizophrenia in 20 to 30% of cases. Those with bipolar disorder are not always in either a manic or a depressive phase; there may be long periods during which they seem virtually symptom-free and do not present disordered thinking, delusions, voices, or other symptoms that characterise psychotic disorders per se. In bipolar disorder, an individual may not always be symptomatic, but during an episode, psychotic schizophrenia-like symptoms are found in the context of mania or depression, these symptoms include delusions of grandeur, hallucinations, wild optimism, grandiose behaviour, as well as physiological abnormalities in the form of a reduced need for sleep, increased appetite, libido and general drive and motivation.
The main distinguishing difference between bipolar disorder and major clinical depression is that in bipolar disorder, manic episodes occur. The existence of one manic episode (meeting DSM IV criteria) is sufficient to make a diagnosis of bipolar disorder. Distinguishing between bipolar disorder and depression is essential for assigning treatment; while depression is treated primarily with anti-depressant medication, bipolar disorder requires a mood-stabilizing medication such as lithium or valproate. Use of anti-depressants in bipolar disorder can sometimes trigger manic episodes.
It can take 6 months or more to make a definitive diagnosis of bipolar disorder, a schizophrenic disorder or other psychosis, because although the symptoms may be evident, it is often difficult to ascertain whether or not the symptoms are being caused by some other neuropsychiatric, neurodegenerative or neurodevelopmental disorder.
There is a need for diagnostic methods and tools that enable schizophrenic conditions and bipolar disorder to be distinguished from other disorders which present with similar symptoms. Differential diagnosis is also needed to exclude psychoses in the context of neurodegenerative and neurodevelopmental disorders as well as organic causes of psychoses, like epileptic and drug-induced psychoses.
The prolonged process currently needed to achieve accurate diagnosis may cause delay of appropriate treatment, which is likely to have serious implications for medium to long-term disease outcome (5; 7; 8). The development of objective diagnostic methods, tests and tools is urgently required to help distinguish between psychiatric diseases with similar clinical symptoms. Objective diagnostic methods, tests for schizophrenia and/or bipolar disorder will assist in monitoring individuals over the course of illness (treatment response, compliance etc.) and may also be useful in determining prognosis, as well as providing tools for drug screening and drug development.
Unfortunately, at present there is no standard, sensitive, specific test for schizophrenia or bipolar disorders.
One biochemical test currently under development for schizophrenia diagnosis is the niacin skin flush test (9-11), based on the observation that there is failure to respond to the niacin skin test in some schizophrenia patients, due to abnormal arachidonic acid metabolism (10). However, the specificity and sensitivity of this test shows an extreme inconsistency between studies, ranging from 23% to 87% (12-15), suggesting that the reliability and validity of this test still need to be verified.
International Patent Application Publication No. WO 01/63294 describes methods and compositions for screening, diagnosis, and determining prognosis of neuropsychiatric or neurological conditions (including BAD (bipolar affective disorder), schizophrenia and vascular dementia), for monitoring the effectiveness of treatment in these conditions and for use in drug development.
Other techniques such as magnetic resonance imaging or positron emission tomography based on subtle changes of the frontal and temporal lobes and the basal ganglia are of little value for the diagnosis, treatment, or prognosis of schizophrenic disorders in individual patients, since the absolute size of these reported differences between individuals with schizophrenia and normal comparison subjects has been generally small, with notable overlap between the two groups (16). The role of these neuroimaging techniques is restricted largely to the exclusion of other conditions which may be accompanied by schizophrenic symptoms, such as brain tumours or haemorrhages.
Therefore, a need exists to identify sensitive and specific biomarkers for differential diagnosis and for monitoring of schizophrenic disorders, bipolar disorders or of predisposition to a schizophrenic or bipolar disorder, in a living subject. Additionally, there is a clear need for methods, models, tests and tools for identification and assessment of existing and new therapeutic agents for the treatment of these conditions.
The VGF gene encodes a neuropeptide precursor which is expressed in a subset of neurons in the central and peripheral nervous system and in specific populations of endocrine cells found in the adenohypophysis, adrenal medulla, gastrointestinal tract and pancreas. Expression of VGF is upregulated in responsive neurons by neurotrophins. VGF is a recognised nerve growth factor and plays an essential role in the regulation of energy homeostasis. The human VGF protein is 615 amino acids in length; the VGF protein in mouse and rat is 617 amino acids in length. There is about 85% homology between the human and rat VGF proteins. The VGF neuropeptide precursor has a secretory leader (“signal”) sequence of 22 amino acids that promotes translocation into the endoplasmic reticulum. In the VGF neuropeptide precursor and the mature full length VGF peptide cleaved from that precursor, there are numerous short stretches of basic amino acid residues, which are potential target sites for peptidase cleavage resulting in the generation of shorter VGF peptides. VGF peptides have been identified in rat and human; Stark et al (2001) (17) identified three N-terminal fragments of VGF (amino acids 23 to 62, 26 to 62 (N-terminal truncation of peptide 23 to 62) and 23 to 59 (C-terminal truncation of peptide 23 to 62)) in human cerebrospinal fluid (CSF) obtained from subjects without known neurological disorders.
VGF peptide biomarkers have been associated with chronic dementia diseases. International Patent Application No PCT/DE02/01376 (WO 02/082075) describes methods for detecting chronic dementia diseases, in particular Alzheimer's disease, involving detection of various VGF-derived peptides, including VGF 23 to 62 and VGF 26 to 62. These diseases are organic disorders. Diagnosis of a chronic dementia disease, such as those described in WO 02/082075, automatically excludes diagnosis of a schizophrenic or bipolar disorder. Until now, there has been no report of a VGF peptide associated with a schizophrenic disorder, bipolar disorder or predisposition thereto.